Work Group Report on the appropriate use of intravenously administered

immunoglobulin (IGIV)

Generated by the primary immunodeficiency committee of the American Academy of

Allergy, Asthma and Immunology.

Participants:

Jordan S. Orange MD, PhD (editor)

Assistant Professor of Pediatrics

University of Pennsylvania School of Medicine

The Children’s Hospital of Philadelphia

3615 Civic Center Blvd – ARC 1216F

Philadelphia, PA 19104

Mark Ballow, MD

Professor of Pediatrics

State University of New York at Buffalo, School of Medicine and Biomedical Sciences

Women's and Children's Hospital of Buffalo

219 Bryant St.

Buffalo, NY 14222

Melvin Berger MD, PhD

Professor of Pediatrics and Pathology

Case Western Reserve University School of Medicine

1

Rainbow Babies and Children's Hospital

11100 Euclid Avenue Mail Stop 6008B, Cleveland, OH

Rebecca H. Buckley, M.D.

J. Buren Sidbury Professor of Pediatrics

Professor of Immunology

Duke University Medical Center

Durham, NC 27710

Javier Chinen, MD, PhD

Associate Investigator

NHGRI-NIH

Bldg 10-CRC, East Wing Rm 6-3340

10 Center Dr. MSC 1611

Bethesda, MD 20892-1611

Charlotte Cunningham-Rundles MD/PhD

Professor, Medicine / Clinical Immunology

Mount Sinai School of Medicine

One Gustave L. Levy Place

Box 1089 New York, NY 10029

Yehia El-Gamal, MD, PhD

President of the Egyptian Society of Pediatric Allergy & Immunolgy (ESPAI)

Professor of Pediatrics

Pediatric Allergy and Immunology Unit

2

Children's Hospital, Ain Shams University

Cairo 11566, Egypt

Elham Hossny, MD, PhD

Professor of Pediatrics,

Pediatric Allergy and Immunology Unit

Children's Hospital, Ain Shams University

Cairo 11566, Egypt

Bruce D. Mazer MD

Division Head,

Allergy and Immunology

Montreal Children�s Hospital

Associate Professor of Pediatrics

McGill University

Robert P. Nelson, Jr. M.D.

Associate Professor of Medicine

Division of Hematology/Oncology

Hematological Malignancy Program/Immunology

Indianapolis, IN

Dhavalkumar D. Patel, MD, PhD

Professor of Medicine and Microbiology and Immunology

Director, Thurston Arthritis Research Center

Chief, Division of Rheumatology, Allergy and Immunology

3

University of North Carolina @ Chapel Hill

CB# 7280, 3330 Thurston Building

Chapel Hill, NC 27599-7280

Elizabeth Secord MD, PhD

Assistant professor of Pediatrics

Wayne State University

Children's Hospital of Michigan

3901 Beaubien

Detroit MI 48201

Ricardo U. Sorensen, M.D.

Department of Pediatrics

Louisiana State University Health Science Center

1542 Tulane Avenue

New Orleans, Louisiana 70112-2822

Richard L. Wasserman, M.D, Ph.D.

Clinical Associate Professor

Department of Pediatrics

University of Texas Southwestern Medical School

7777 Forest Lane, B-332

Dallas, Texas 75230

Catherine R. Weiler, MD, PhD

Assistant Professor of Medicine

4

W-15 Mayo Bldg

Division of Allergy

Mayo Clinic College of Medicine

Rochester, MN 55905

5

Introduction

Immunoglobulin (IG) for intravenous (IV) administration, or IGIV (also commonly

referred to as IVIG, although officially designated in the US as IGIV) is currently approved

by the US Food and Drug Administration (FDA) for 6 indications: 1) treatment of primary

immunodeficiencies; 2) prevention of bacterial infection in patients with

hypogammaglobulinemia due to B cell chronic lymphocytic leukemia; 3) prevention of

coronary artery aneurysms in Kawasaki disease; 4) prevention of infections and graft

versus host disease after bone marrow transplantation; 5) reduction of serious bacterial

infection in HIV-infected children; and 6) increasing platelet count in idiopathic

thrombocytopenic purpura to prevent bleeding. Not all currently available products are

approved for each of these indications and physicians should review specific product

information. The use of IGIV for these purposes can be variable and there are notable

disparities in current clinical practices. Furthermore, there have been developments

regarding IGIV usage, which warrant consideration.

IGIV has been utilized for other conditions without FDA approval. Some of these

uses are based entirely upon theory and/or anecdotal reports, while others are based upon

quality evidence. A comprehensive review of the evidence supporting the use of IGIV in

specific indications is beyond the scope of this document, but was reviewed in detail in its

preparation. The entire summary of evidence and detailed recommendations regarding

the use of IGIV will be published elsewhere and the reader is referred to that document as

well as other more comprehensive discussions of IGIV usage.1

In this position statement the major uses of IGIV are reviewed and specific

recommendations are provided where appropriate (Table 1). These recommendations

should not be considered absolute, but should help prompt each prescribing physician to

6

consider and review the data supporting any particular use of IGIV. The indications

discussed are: primary immunodeficiency; secondary immunodeficiency; autoimmune

disease; asthma; neurologic disorders; transplantation; infectious disease; Kawasaki

disease; and other uses. Practical considerations in using IGIV are also raised.

Primary Immunodeficiency

IGIV is indicated to reduce the susceptibility to infections in patients with primary

immunodeficiencies affecting the quantity and/or quality of humoral immunity. Primary

humoral immunodeficiencies include agammaglobulinemia, hyper IgM syndrome, common

variable immunodeficiency as well as other deficiencies of immunoglobulin and specific

antibody production (hyper IgE syndrome, Wiskott-Aldrich Syndrome and specific antibody

deficiency).2 Patients markedly deficient in humoral immunity are dependent on IGIV for

survival. Benefits of IGIV in patients not able to produce antibodies normally include: a

reduction of the severity and frequency of infections,3 prevention of chronic lung disease4

and prevention of enteroviral meningoencephalitis.3 The decision to administer IGIV to

patients with primary deficiencies in antibody production should be based on: 1)

abnormalities of serum immunoglobulin concentrations; 2) clinical history of infections;

and, when appropriate, 3) the demonstrated inability to produce antibody normally

following antigenic stimulation. IGIV is not indicated for treatment of selective IgA

deficiency, per se, but may be useful in patients in whom IgA deficiency is accompanied by

defects in IgG production.

An additional consideration is the route of administration. In the United States, at

the present time, available immunoglobulin products are licensed only for administration by

the intravenous or intramuscular route. Subcutaneous administration of intravenous or

intramuscular preparations of immunoglobulin which is widely employed in Europe, has

therapeutic equivalence with intravenous therapy.5, 6

7

Secondary immunodeficiency

IGIV has also been used in a number of diseases that result in secondary

immunodeficiency. IGIV administration may be appropriate for selected patients with B

cell chronic lymphocytic leukemia.7 A well controlled trial of IGIV in HIV infected children

demonstrated a significant reduction in bacterial infections but the benefit of IGIV was not

seen in patients treated with trimethoprim/sulfamethoxazole for Pneumocystis pneumonia

prophylaxis.8 The use of IGIV as an adjunct to enhance the antibacterial defenses of

premature newborn infants remains controversial, but may diminish the incidence of

sepsis.9 Other uses of IGIV for secondary immunodeficiencies, including sepsis beyond

the neonatal period, multiple trauma and post-operative wounds are not well supported by

published data.

Autoimmune Diseases

IGIV remains an important treatment modality in immune thrombocytopenic

purpura, and it has been shown to improve platelet counts in controlled studies.10 Despite

the lack of vigorous scientific evidence for benefit in post-transfusion purpura, IGIV

administration is recommended given the potential life threatening nature of the disease.11

Anecdotal reports also suggest utility for IGIV in autoimmune neutropenia, autoimmune

hemolytic anemia, Evans syndrome and acquired hemophilia especially when other

therapeutic modalities fail.12, 13

IGIV has been used with varying efficacy in several other autoimmune diseases.

The results in rheumatoid arthritis are controversial, but some benefit was suggested from

case reports and open label trials.14 Although high dose IGIV was reported to improve

specific organ-related complications of systemic lupus erythematosus including nephritis,

myocarditis, polyradiculopathy, and bone marrow suppression, its potential

8

prothromboembolic effects necessitate extreme caution in its therapeutic application.15

IGIV also anecdotally helped patients with antiphospholipid antibody syndrome

experiencing recurrent spontaneous abortion and those undergoing in vitro fertilization.16

Some case reports and open label studies additionally report benefit from IGIV as an

alternative therapeutic agent in patients with anti-neutrophil cytoplasmic antibody

disorders,17 systemic sclerosis/scleroderma,18 and Still's disease.19 IGIV has been

successfully used in some other organ specific autoimmune diseases including Graves'

opthalmopathy,20 autoimmune uveitis,21 and autoimmune chronic active hepatitis,22 but

lack of convincing evidence prevents a recommendation for its routine use.

Asthma

Asthma is a disease of pulmonary inflammation, which is effectively treated in most

individuals with regimens that include low to moderate doses of inhaled corticosteroids, or

non-steroidal anti-inflammatory agents. In some patients, very high doses of inhaled and

oral steroids are required to control asthma symptoms, leading to intolerable adverse

effects. In this setting, IGIV has been employed as a steroid-sparing agent in open trials.23-

26 Two placebo-controlled studies have had contradictory results; one failed to show any

benefit of IGIV,27 while the other demonstrated decreases in steroid requirements in

steroid-dependent asthmatics.28 Other smaller studies that have used low doses of IGIV,

or that have only evaluated patients requiring inhaled steroids have not shown significant

differences.26, 29

The inconsistent data from randomized controlled studies combined with the cost

and availability of IGIV, does not support a recommendation for routine use in severe

asthma. The efficacy in select groups, suggests that it may be used as a treatment for

carefully defined asthmatic patients with persistent requirements for high doses of

systemic steroids. Although, IGIV cannot be presently recommended for routine treatment

9

of asthma, individuals with antibody deficiency who have asthma-like symptoms can

benefit from IGIV therapy through its ability to decrease the incidence of infections that

may trigger bronchospasm.

Neurological Disorders

IGIV has demonstrated effectiveness in inflammatory demyelinating disorders of the

peripheral and central nervous systems.30, 31 Despite the lack of an FDA indication, IGIV

has become first-line therapy for demyelinating neuropathies such as Guillain-Barre

syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor

neuropathy, and has demonstrated similar efficacy with less adverse effects than plasma

exchange or corticosteroids.32-34 In myasthenia gravis35 and Lambert Eaton myasthenic

syndrome,36 IGIV may be used as an alternative treatment when patients fail to respond or

do not tolerate other treatments. IGIV may also be a potentially effective second line

treatment in relapsing-remitting multiple sclerosis, although the optimal dosage remains to

be established.37 IGIV may also be extremely useful in the inflammatory myopathies,

polymyositis and dermatomyositis,38 but it is unlikely to be beneficial in inclusion body

myositis39 and thus a specific recommendation for use in the latter disease in particular is

not possible.

Due to the paucity of reliable studies that demonstrate substantial efficacy of IGIV in

intractable childhood epilepsy syndromes, its routine use cannot be recommended for

these patients. However, the poor prognosis and quality of life of children who do not

improve with anti-epileptic drugs and corticosteroids would justify a role for IGIV especially

in patients who may be candidates for surgical resection.40, 41 Many case reports exist in

which IGIV therapy was tried with varying success in other less common neurological

disorders but more clinical research is needed to establish its usefulness.

10

Hematopoietic Stem Cell and Solid Organ Transplantation

IGIV is currently indicated as an adjunct treatment for selected patients undergoing

allogenic hematopoetic stem cell transplantation for the treatment of hematologic

malignancy.42 Treatment is provided to prevent infection during the period in which

patients are rendered most immunodeficient due to chemoablation, typically during the first

100 days. Similarly IGIV is effective in the management of primary immunodeficient

patients undergoing allogeneic transplantation.43 In particular, IGIV offers protection

against interstitial pneumonia secondary to CMV, especially when given in conjunction

with antiviral chemoprophylaxis.44

The benefit of IGIV as adjunct therapy for patients transplanted in the era of

improved molecular HLA matching, anti-CMV chemoprophylaxis, gram-negative

antimicrobial prophylaxis, nonablative conditioning regimens and improvements in graft

versus host immunoprophylaxis is not known. Thus, a re-evaluation of practices is

warranted. In this regard a recent double-blind placebo-controlled multi-center trial of IGIV

in allogeneic bone marrow transplantation failed to demonstrate utility of IGIV

administration.45 As a result, its routine use in patients undergoing allogeneic matched

related bone marrow transplantation may not be necessary.

IGIV had also been considered to reduce the incidence and severity of acute graft

versus host disease (GVHD).46 More recent studies, however have failed to demonstrate

this benefit, thus preventing a recommendation of IGIV for this indication.42, 45 In contrast,

data have never supported the use of IGIV to prevent chronic GVHD.47 Further trials are

needed to resolve data supporting contrasting practices. Studies are also needed to

determine whether IGIV is beneficial in the case of HLA-matched unrelated donor bone

marrow or cord blood transplants.

IGIV can be useful for solid organ transplant recipients who experience acute

rejection, or who are HLA-sensitized for acute rejection, and may be justified for

11

appropriately selected renal transplantation.48 Although less data exist, there may also be

a role for IGIV in autoimmune cytopenias that can occur post-transplant.49

Kawasaki Disease (KD)

KD is an acute febrile vasculitis of medium-sized vessels that commonly affects the

coronary arteries and is believed to have a post-infectious origin. IGIV (single dose of

2g/kg) in conjunction with aspirin is the standard of care for patients with KD during the

first 10 days of the syndrome to prevent the development of coronary aneurysms.50

Although there are some data suggesting that there may be benefit to treatment on or prior

to day 5,51 they have been challenged.52 Most importantly, therapy should be provided

when the diagnosis is established in attempt to prevent coronary aneurysm, even after 10

days of onset of fever.

Treatment of infectious disease

Although IGIV does not have a major role in the treatment of infections, a beneficial

role has been shown in the following settings. Adjunct treatment of established bacterial

septic shock and neonatal group B streptococcal disease with IGIV provides benefit and

reduces mortality.53-57 High dose IGIV administered intravenously or intrathecally may be

useful for treatment of meningoencephalitis caused by enteroviral infection in patients with

agammaglobulinemia.58 Orally administered IGIV can reduce the duration of diarrhea, viral

shedding and hospitalization in children with acute rotaviral gastroenteritis.59 Treatment of

pneumonitis caused by CMV with high dose IGIV,60 or high-titer anti-CMV IGIV44 combined

with ganciclovir has resulted in improved outcomes. IGIV or hyperimmune respiratory

syncytial virus (RSV) IGIV has provided some benefit in combination with ribavirin to treat

RSV pneumonitis in immunodeficient patients.61, 62 IGIV has also been effectively

administered in anemia caused by chronic erythrovirus B-19 infection,63 Campylobacter

12

jejuni infection,64 and in pseudomembneous colitis caused by Clostridium difficle,65 but its

widespread use in these conditions is not supported by extensive data.

Other Uses

Conflicting reports exist regarding the efficacy of IGIV in toxic epidermal necrolysis

and Stevens-Johnson syndrome, but given the risk of mortality, the majority of evidence

support the use of high-dose IGIV as an early therapeutic intervention.66 The evidence for

IGIV use in the autoimmune blistering disorders, such as bullous pemphigoid, is outlined in

a consensus statement published by the American Academy of Dermatology,67 and is

primarily based on case reports or prospective studies of �last resort� treatment. There

has been an open trial of IGIV use for delayed pressure urticaria and two thirds of the

patients had remission, or some benefit.68 The evidence for IGIV use in other chronic

urticarias is unclear and does not currently support its use.69, 70 Likewise the data for

atopic dermatitis, which includes one small, randomized, evaluator blinded trial, does not

support the use of IGIV.71 There are case reports, but no controlled trials supporting the

use of IGIV in psoriasis.72

Several neurocognitive disorders are proposed to have immunological components

including childhood autism, chronic fatigue syndrome and the pediatric autoimmune

neuropsychiatric disorders with associated streptococcal infection (PANDAS). Despite the

abundance of anecdotal reports of IGIV utility in these disorders, a double-blind placebo

controlled trial has only been performed in chronic fatigue syndrome and demonstrated a

lack of efficacy.73 In PANDAS, a single case controlled prospective trial did demonstrate

efficacy of 1g/kg/d treatment with IGIV on 2 consecutive days for rigorously defined

patients.74 In contrast, studies of IGIV in autism have at best, been case series and have

not provided suggestion of benefit.75

13

IGIV has also been evaluated in certain other organ specific diseases. In selected

patients with cystic fibrosis there have been some encouraging observations regarding

IGIV therapy, but effects are marginal and probably do not justify the resources and risk.76

High dose IGIV treatment appeared promising in numerous case reports of acute

myocarditis,77 but has been found ineffective in treatment of the carditis of acute rheumatic

fever78 as well as in recently diagnosed dilated cardiomyopathy,79 as determined by

randomized placebo controlled trials. Finally, IGIV has been suggested to promote

successful pregnancy in women who experience recurrent spontaneous abortion, but

meta-analysis of existing randomized controlled trials failed to demonstrate any benefit80

and thus therapy is not recommended for this indication.

IGIV Products

There are currently a number of IGIV products that provide chemically unmodified

lyophilized or liquid forms of IgG produced from plasma recovered from whole blood

donations or from plasmapheresis donors (Table 2). Lots may contain plasma obtained

from more than 50,000 donors, which is pooled and then treated to precipitate the

immunoglobulin-containing fraction. The resulting solutions may contain sodium,

maltose, albumin, polyethylene glycol, D-mannitol, D-sorbitol, sucrose, glucose, and/or

albumin among other substances to prevent aggregation. Donors are screened and

tested for multiple infectious agents to reduce the risk of pathogen contamination. In

addition, several different pathogen inactivation steps are also utilized in the preparation

of the various IGIV products and can include solvent/detergent treatment, acid incubation,

pasteurization, filtration, and precipitation/chromatography. IGIV solutions have final IgG

concentrations of 3,5,6,10 or 12% depending on the product. The osmolarity of these

solutions lies between 253 mOsm/L and 1250 mOsm/L. The IgA content of current brands

varies between <0.4µg/ml to 720 µg/ml.

14

IGIV dosing

For antibody replacement IGIV therapy is typically administered every 3 to 4 weeks

starting with as much as 400-600 mg/kg.81 The dose or dosing interval should be

adjusted (based on the clinical response and patient�s catabolism of IgG or known protein

loss) to achieve optimal clinical results. Some studies suggest that doses as high as 800

mg/kg/month may be useful, particularly in primary immunodeficiency patients with

chronic lung disease.82, 83 Measurement of trough IgG levels may be helpful. Trough

levels greater than 500 mg/dl are associated with fewer infections and improved

outcomes.3, 84 The target trough level for patients with pre-treatment IgG levels between

200 and 500mg/dl should be at least the pre-treatment IgG plus 300. Higher trough levels

(>800 mg/dL) have the potential to further reduce the incidence of infection.3 Patients

with normal IgG levels, but impaired specific antibody production may also benefit from

doses ≥400mg/kg.85 Ultimately, the dose must be individualized and titrated to achieve

clinical benefit for the patient being treated. Immunomodulatory doses are typically higher

than those used for antibody replacement and range between 400 mg/ kg for 5 days, or a

more rapid course of 1 or 2 g/kg given in one or two days.

Infusion methods

The first infusion in an immunodeficient patient should be given in a setting with

cardiovascular and pulmonary monitoring and should be administered slowly, starting with

a rate of 0.4 mg/Kg/min. After 15 to 30 minutes the rate can be increased to 1.2 to 1.6

mg/Kg/min, and increased as tolerated to a maximum of 3.3 mg/kg/min (certain IGIV

products are licensed for greater rates of infusion). Considerations of the sodium or

sucrose content, total volume to be administered, and the osmolarity of the product are

important in patients with pre-existing medical conditions such as renal86 or

15

cardiovascular disease.31, 87-89 IGIV preparations should not be considered to be

generically equivalent, and substitution should generally not be allowed without careful

monitoring of the patient. Infusions of IGIV are commonly given in outpatient infusion

centers, outpatient clinics, or in the home. The latter is facilitated by the involvement of

home care nurses, but alternatively can be provided by self infusion.90 The placement and

use of indwelling venous access for IGIV administration should be carefully weighed

against the thrombotic and infectious risks inherent to these devices that may be further

amplified in immunodeficient patients, or by administration of IGIV. In most cases the IV

route is used, but subcutaneous infusion (not yet FDA approved), has been found

similarly satisfactory at least in primary immunodeficiency.91 This route may be especially

useful in patients with difficult venous access. Although a number of protocols are

applicable for subcutaneous immunoglobulin replacement therapy, 100mg/kg/wk is an

acceptable option as a starting dose. Typically, up to 20cc of IGIV (or intramuscular IG) is

infused into a single site at rates approximating 10cc/hr. Multiple sites may be used

simultaneously as well as the more concentrated preparations of IGIV to allow for an

efficient infusion process. The subcutaneous route of administration, however, has not

been well documented for indications other than primary immunodeficiency and should be

avoided for the treatment of other diagnoses until better data are available.

Adverse effects

Mild adverse reactions, myalgias, chills, low grade fever, and/or headache are

relatively common. They occur more commonly in the first few infusions and are treated

by slowing or stopping the infusion for 15 to 30 minutes. Pre-treatment with

diphenhydramine, acetaminophen, aspirin or ibuprofen, or IV hydration may also be

helpful. Prophylaxis of more severe reactions can be provided with 1mg/kg IV

hydrocortisone. Serious adverse events are rare, but include aseptic meningitis, renal

16

failure, thrombosis, and perhaps neurodegeneration amongst others.92 Of these, renal

failure has been associated with the sucrose content of a given product and thrombosis

may be associated with high osmolarity products or high viscosity states.90, 93 There is

also a risk of reactions from anti-IgA antibodies generated in patients with complete IgA

deficienc,94 including true IgE-mediated anaphylactic reactions against IgA,95 but the latter

are extremely rare. The risk of these reactions and/or the risk of sensitization of IgA

deficient patients with some preserved antibody production may be minimized by selection

of IGIV products with low IgA content. Finally, the theoretical and actual possibility of

transmission of blood-borne infection needs to be considered. Thus, the risks of IGIV

administration must be carefully weighed against potential benefits. The appropriate use

of IGIV, however, can be life-saving and should not be withheld for patients in justifiable

need.

17

Literature cited

Table 1: Selected uses of IGIV*

Benefit* Disease Evidence category*** Reference

Definitely beneficial

Primary immunodeficiency Idiopathic thrombocytopenic purpura Graves� ophthalmopathy Demyelinating polyneuropathies Kawasaki Disease

IIb Ia Ib Ia Ia

2,3 10 20 30, 32-34 50

Probably beneficial

Chronic lymphocytic leukemia with reduced IgG and history of infections Prevention of bacterial infection in HIV-infected

children Dermatomyositis and polymyositis Myasthenia Gravis and Eaton-Lambert myasthenia Established bacterial sepsis Toxic epidermal necrolysis and Stevens-Johnson

Syndrome

III Ib IIa Ib Ia IIa

7 8 38 35,36 53-57 66

May provide benefit

Prevention of neonatal sepsis Post transfusion purpura Autoimmune cytopenias Systemic Lupus Severe rheumatoid arthritis Antiphospholipid antibody syndrome in pregnancy Anti-neutrophil cytoplasmic antibody syndromes Severe persistent high dose steroid-dependent asthma Multiple sclerosis (relapsing-remitting) Intractable childhood epilepsy Prevention of infection and acute graft versus host disease post-hematopoetic stem cell transplantation Prevention of acute humoral rejection in renal transplantation

Ia III III III IIb III III Ib Ia Ia Ib III

9 11 12 15 14 16 17 23-27 37 40, 41 42, 43, 45, 46 48

Benefit* Disease Evidence category*** Reference

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)

IIb

74

Unlikely to be beneficial

Inclusion body myositis Non steroid-dependent asthma Atopic Dermatitis Chronic non-pressure urticarias Chronic fatigue syndrome Autistic disorders

Ib Ib IIa IIb Ia III

39 26-29 71 69, 70 73 75

*Indications for which certain IGIV products have approval from the US Food and Drug Administration are listed in boldface italics.

**The recommendation of benefit is based upon the available evidence. As additional studies become available and as the category of evidence listed for a given indication changes it is possible that the benefit category will change. The strength of a recommendation within a given category should be considered directly proportional to the category of evidence.

***Evidence categorization is as follows: Ia � from meta-analysis of randomized controlled studies; Ib � from at least one randomized controlled study; IIa � from at least one controlled trial without randomization; IIb - from at least one other type of quasi-experimental study; III � from non-experimental descriptive studies such as comparative, correlation or case-control studies; IV � from expert committee reports or opinions or clinical experience of respected authorities or both. It should be clear that this scale is non-linear and recommendations based on category I evidence should be given the greatest value.

Table 2: Currently Available IGIV Products and Their Properties

Product Dosage Form Diluent Refrigeration

Filter Required

Osmolality (mOsm/L) Sodium Content

pH after

Reconstitution

IgA content

Stabilizer, or added regulator

Indication****

Carimune NF

Lyophilized powder

0.9% sodium chloride

No No 498 (3%) 690 (6%) 1,074 (12%)

0.01 mEq/mL (3% solution) 0.02 mEq/mL (6% solution) 0.041 mEq/mL (12% solution)

6.6 720µg/ml Sucrose PI, ITP

Carimune NF

Lyophilized powder

Sterile Water for Injection

No No 192 (3%) 384 (6%) 576 (9%) 768 (12%)

none 6.6 720µg/ml Sucrose PI, ITP

Flebogamma

5% Liquid NA No*** Optional 240-350 <0.032 mEq/ml 5-6 <0.05mg/ml

D-sorbitol PI

Gamimune N 10%*

10% liquid NA Incompatible with saline

Yes No 274 Trace 4.25 Glycine PI, ITP, BMT, HIV

Gammagard 5% S/D

Lyophilized powder

Sterile Water for Injection

No Yes 636 (5%) 0.145 mEq/mL

6.8 <2.2µg/ml 2% Glucose PI, ITP, CLL, KD

Gammagard 10% S/D

Lyophilized powder

Sterile Water for Injection

No Yes1,250 (10%)

0.145 mEq/mL 6.8 270µg/ml 4% Glucose PI, ITP, CLL, KD

Gammar-P Lyophilizedpowder

Sterile Water for Injection

No No 309 (5%) 0.085 mEq/mL 600 (10%)

6.8 <25µg/ml Sucrose PI

Gamunex 10% Liquid NA Incompatible with saline

No** No 258 Trace 4 to 4.5 46µg/ml Glycine PI

Iveegam EN**

Lyophilized powder

Sterile Water for Injection

Yes Yes ≥ 240 0.05 mEq/mL 6.4 to 7.2 <10µg/ml Glucose PI, KD

Octagam 5% liquid NA No*** No 310-380 0.03 mEq/ml 5.1-6.0 <0.1mg/ml Maltose PIPanglobulin NF

Lyophilized powder

(0.9% sodium chloride, 5% dextrose,) Sterile Water for Injection

No No With water: 0.01 mEq/mL (3% solution) 192 (3%)* 384 (6%)* 576 (9%)* 768 (12%)*

0.02 mEq/mL (6% solution) 0.031 mEq/mL (9% solution) 0.041 mEq/mL (12% solution)

or none

6.6 720µg/ml Sucrose PI, ITP

Polygam S/D

Lyophilized powder

Sterile Water for Injection

No Yes 636 (5%) 0.145 mEq/mL (5% solution) 1,250 (10%)

0.28 mEq/mL (10% solution) 6.8 <2.2µg/ml Glucose PI, ITP, CLL,

KD

*Gamimune N has been discontinued but may still be offered by suppliers as inventories may still exist. **Iveegam EN is currently only available for patients who have been maintained on this product. ***not required ****US Food and Drug Administration Licensed indications for the specific product. Abbreviations are: PI, primary immunodeficiency; ITP � immune thrombocytopenic purpura; BMT � bone marrow transplantation; KD � Kawasaki disease; HIV � pediatric HIV infection; CLL � B-cell chronic lymphocytic leukemia. For specifics of each indication please see the text and the manufacturers product information. NA � Not applicable

1. Sacher RA. Intravenous immunoglobulin consensus statement. J Allergy Clin Immunol 2001; 108:S139-46.

2. Buckley RH, Schiff RI. The use of intravenous immune globulin in immunodeficiency diseases. N Engl J Med 1991; 325:110-7.

3. Quartier P, Debre M, De Blic J, de Sauverzac R, Sayegh N, Jabado N, et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr 1999; 134:589-96.

4. Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol 2002; 109:1001-4.

5. Gardulf A, Andersen V, Bjorkander J, Ericson D, Froland SS, Gustafson R, et al. Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs. Lancet 1995; 345:365-9.

6. Chapel HM, Spickett GP, Ericson D, Engl W, Eibl MM, Bjorkander J. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J Clin Immunol 2000; 20:94-100.

7. Cooperative group for the study of immunoglobulin in chronic lymphocytic leukemia. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. N Eng J med 1988; 319:902-7.

8. Mofenson LM, Moye J, Jr., Korelitz J, Bethel J, Hirschhorn R, Nugent R. Crossover of placebo patients to intravenous immunoglobulin confirms efficacy for prophylaxis of bacterial infections and reduction of hospitalizations in human immunodeficiency virus-infected children. The National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group. Pediatr Infect Dis J 1994; 13:477-84.

9. Ohlsson A, Lacy J. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. Cochrane Database Syst Rev 2004; 1:CD001239.

10. Godeau B, Chevret S, Varet B, Lefrere F, Zini JM, Bassompierre F, et al. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial. Lancet 2002; 359:23-9.

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